Synthetic Lethality As an Engine for Cancer Drug Target Discovery

REVIEWS Synthetic lethality as an engine for cancer drug target discovery Alan Huang1, Levi A. Garraway2,4, Alan Ashworth3 and Barbara Weber 1* Abstract | The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR- based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers. Cancer is a disease of the genome, and almost all can cancer24,25, EGFR mutations and ALK translocations in cers have multiple genetic lesions that must be addressed non smallcell lung cancer (NSCLC)26–35 and numerous to develop curative combination therapies1. A reduc others36. However, our ability to make further progress tionist view of the hallmarks of cancer suggests that tar with genetically targeted cancer therapy has been limited geting oncogenic drivers, tumour suppressor gene loss by two main issues. First, although partial responses to and the underlying mechanisms by which cancer cells targeted therapies in selected patient populations are evade immune destruction are the minimum that will common, converting those partial responses to dura be required for cures1. ble complete responses, which is needed for cures, will Completion of the Human Genome Project in 2003 require combination regimens that have been challeng (REFS2,3) followed by advances in sequencing technol ing to define. Additionally, although DNA sequencing ogy and the analysis of thousands of human tumours4–7 technology has enabled the identification of most, if enabled discovery of the first generation of genetically not all, oncogenes that arise as a consequence of genetic targeted cancer therapies, which, even as single agents, alterations37–39, they represent a relatively small percent changed the lives of many people with cancer. Imatinib, age of genes that are relevant in cancer, not all of which which targets the BCR–ABL fusion tyrosine kinase, has are druggable with conventional approaches. Proteolysis- extended the median survival of patients with chronic targeting chimaeras (PROTACS) and other protein myelogenous leukaemia to more than 10 years8–11. degradation approaches are likely to change the definition Imatinib also inhibits KIT and is effective in treating of ‘druggable’ in the coming years40,41, but independent of 1Tango Therapeutics, KIT mutant gastrointestinal stromal tumours, with advances that may redefine druggability, identification Cambridge, MA, USA. response rates of up to 50% and a median progression- of the next wave of cancer drug targets requires more than 2Eli Lilly and Company, free survival of approximately 18 months12–15. The deep sequencing of multiple tumours. CRISPR enabled Indianapolis, IN, USA. BRAF inhibitor vemurafenib16, followed a few years functional genomic screening platforms are powerful tools 3UCSF Helen Diller Family later by dabrafenib17 and encorafenib18, transformed for this application. Comprehensive Cancer BRAF mutant melanoma from an untreatable, rapidly As enthusiasm for targeted cancer therapy waned Center, San Francisco, CA, USA. progressive malignancy to a disease in which more than somewhat in the face of its limitations, progress harness 50% of patients have meaningful clinical responses19,20 ing the immune system to treat cancer allowed another 4Present address: Roche/Genentech, South and when combined with a MEK inhibitor, have a wave of clinically meaningful responses, and, in some San Francisco, CA, USA. median progression free survival of approximately cases, cures. Many patients with melanoma, regardless 21–23 42–44 45 *e- mail: [email protected] 12 months with limited toxicity . There are multiple of BRAF mutation status , renal cell carcinoma , 46–49 50 https://doi.org/10.1038/ other examples of clinical successes, including drugs NSCLC and a number of other cancers have clin s41573-019-0046-z that target amplified ERBB2 (encoding HER2) in breast ically meaningful responses to checkpoint inhibitors NATURE REVIEWS | DRUG DISCOVERY REVIEWS such as anti programmed cell death 1 (PD1) or anti- decade. Here we analyse the evidence that many cancer PD1 ligand 1 (PD L1), as well as in some cases antibod targets remain to be discovered using a CRISPR based ies against cytotoxic T lymphocyte antigen 4 (CTLA4), functional genomic screening and how this approach alone or in combination with another checkpoint can lead to the discovery of additional targets based on inhibitor51,52. These important successes further damp loss of tumour suppressor genes. We also highlight the ened enthusiasm for genetically targeted therapies and importance of genetic context in designing target discov spurred a wave of clinical investigation in a broad range ery strategies, and analyse the technical considerations of tumour types with many putative immune cell tar for scalable synthetic lethal target discovery, including gets. This next wave of immunotherapy agents has yet to the relative benefits of various CRISPR based tools prove as effective as anti PD1 and anti PDL1 agents53, and libraries, discussing inhibition of protein arginine and it remains to be determined whether immunother N methyltransferase 5 (PRMT5) in cancers with dele apies will do what the initial targeted therapies failed to tion of S methyl5′thioadenosine phosphorylase do: to produce durable complete responses and cures in (MTAP) as an example of targeting synthetic lethality large numbers of patients with cancer. beyond poly(ADPribose) polymerase (PARP) inhibitors Therefore, although advances in both targeted therapy in BRCA1mutant and BRCA2mutant contexts. Finally, and immunotherapy have improved cancer treatment we discuss the applications of CRISPR based screening for many people in remarkable ways, barriers to target with targeted drugs for novel combination discovery and ing tumour suppressor gene loss, identifying context- in vivo screening for noncell autonomous mechanisms. dependent driver genes that are not marked by genetic alterations (which result in non oncogene addiction54,55, Synthetic lethality called here ‘unmarked oncogenes’), designing the next The genetic concept of synthetic lethality was first generation of novel combinations and exploring the described in Drosophila in 1922 (REFS56,60–62). Fruit flies largely unknown genetics of tumour intrinsic immune with individual abnormal eye phenotypes (phenotypes evasion have stalled progress. However, the genetic prin that were attributed to either Bar or glass mutations) ciple of synthetic lethality coupled with the power of could survive and reproduce but viable offspring with a CRISPRbased functional genomic screening technology combination phenotype were never observed56. We now offers a path forward. know that Bar and glass encode transcription factors Synthetic lethality, initially described in Drosophila expressed in the eye, an extension of the central nervous as recessive lethality56, is classically defined as the setting system, and are involved in embryonal development. We in which inactivation of either of two genes individually can therefore postulate that loss of both genes simultane has little effect on cell viability but loss of function of ously results in neural development defects not compat both genes simultaneously leads to cell death. In can ible with life, although the specific lethality mechanism cer, the concept of synthetic lethality has been extended of this synthetic lethal pair has not been studied directly. to pairs of genes, in which inactivation of one by dele The concept was subsequently also shown to be relevant tion or mutation and pharmacological inhibition of the in yeast63, and eventually was proposed as a basis for other leads to death of cancer cells whereas normal cells drug discovery for human disease by Hartwell, Friend (which lack the fixed genetic alteration) are spared the and colleagues 20 years ago57. Hartwell, and subsequently effect of the drug. In the most straightforward applica Kaelin, proposed that novel targets for cancer therapeu tion, this means identifying targeted therapies that kill tics could be discovered by exploiting the concept of syn cancer cells that lack a specific tumour suppressor gene thetic lethality, in which one member of a synthetic lethal but spare normal cells. In addition to this (conceptu pair is a gene product with a cancer specific mutation ally) simple application, the tools needed to discover and the second gene product is the drug target57,58. synthetic lethal interactions in human cancer cells can The systematic identification of synthetic lethal pairs be applied in multiple ways to identify a number of other relevant to human

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